The invention relates, as new and useful industrial products, to biaromatic compounds which are analogues of vitamin D. It also relates to the process for their preparation and their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological conditions (and the like) linked to a keratinization disorder, of conditions with an inflammatory and/or immunoallergic components and of hyperproliferation of tissues of ectodermal origin (skin, epithelium and the like), whether benign or malignant. These compounds may, in addition, be used to combat skin ageing, whether photoinduced or chronologic, and to treat cicatrization disorders.
It is also possible to use the compounds according to the invention in cosmetic compositions for body and hair hygiene.
Vitamin D is an essential vitamin for the prevention and treatment of defects in the mineralization of cartilage (rickets), and of bone (osteomalacia), and even of certain forms of osteoporosis in the elderly subject. However, it is now accepted that these functions extend well beyond the regulation of bone metabolism and of calcium homeostasis. Among these, there may be mentioned its actions on cell proliferation and differentiation and the control of the immune defences. Their discovery has opened the way for new therapeutic approaches in dermatology, cancerology as well as in the field of autoimmune diseases and that of organ and tissue transplants.
An effective therapeutic application has for long been hampered by the toxicity of this vitamin (hypercalcaemia which is sometimes fatal). Currently, structural analogues of vitamin D are synthesized, some of which conserve only the differentiating properties and have no action on calcium metabolism.
One of the aims of the present invention is to provide new compounds which are structural analogues of vitamin D, which show a selective activity on cell proliferation and differentiation without exhibiting a hypercalcaemic character.
Another aim of the present invention is to provide new compounds which are analogues of vitamin D, which are easier to synthesize and therefore more economical compared to what was previously known.
Thus, the present invention relates to compounds which may be represented by the following general formula (I): 
in which:
R1 represents a hydrogen atom, a methyl radical or a radical xe2x80x94(CH2)nxe2x80x94OR7,
R2 represents a radical xe2x80x94(CH2)nxe2x80x94OR8,
n, R7 and R8 having the meanings given below,
Xxe2x80x94Y represents a bond chosen from the bonds of the following formulae (a) to (d) which may be read from the left to the right or conversely: 
R9 and W having the meanings given below,
R3 represents the chain in vitamin D2 or in vitamin D3, 
the dotted lines represent the bond linking the chain to the benzene ring represented in Figure. (I),
or R3 represents a chain having from 4 to 8 carbon atoms which is substituted with one or more hydroxyl groups, it being possible for the hydroxyl groups to be protected in the form of acetoxy, methoxy or ethoxy, trimethylsilyloxy, tert-butyldimethylsilyloxy, tetrahydropyranyloxy and optionally in addition:
which is substituted with one or more lower alkyl groups or cycloalkyl groups and/or
which is substituted with one or more halogen atoms and/or
which is substituted with one or more CF3 groups and/or
in which one or more carbon atoms of the chain are replaced by one or more oxygen, sulphur or nitrogen atoms, it being possible for the nitrogen atoms to be optionally substituted with lower alkyl radicals and/or
in which one or more single bonds of the chain are replaced by one or more double and/or triple bonds,
R3 being positioned on the benzene ring at the para or meta position with respect to the Xxe2x80x94Y bond,
R4, R5 and R6, which are identical or different, represent a hydrogen atom, a lower alkyl radical, a halogen atom, a radical xe2x80x94OR10, a polyether radical,
R10 having the meaning given below,
n being 0, 1 or 2,
R7 and R8, which are identical or different, represent a hydrogen atom, an acetyl radical, a trimethylsilyl radical, a tert-butyldimethylsilyl radical, a tetrahydropyranyl radical,
R9 represents a hydrogen atom or a lower alkyl radical,
W represents an oxygen atom, a sulphur atom, a radical xe2x80x94CH2xe2x80x94 or a radical xe2x80x94NHxe2x80x94 which may be optionally substituted with a lower alkyl radical,
R10 represents a hydrogen atom or a lower alkyl radical.
The invention also relates to the optical and geometric isomers of the said compounds of formula (I) as well as their salts in the case where Xxe2x80x94Y represent a bond of formula (a) and W represents a radical xe2x80x94NHxe2x80x94 optionally substituted with a lower alkyl radical.
When the compounds according to the invention are provided in the form of salts, by addition of an acid, these are pharmaceutically or cosmetically acceptable salts obtained by addition of an inorganic or organic acid, in particular hydrochloric, sulphuric, acetic, fumaric, hemisuccinic, maleic and mandelic acid.
According to the present invention, lower alkyl radical is understood to mean a linear or branched radical having from 1 to 6 carbon atoms, and preferably the methyl, ethyl, isopropyl, tert-butyl and hexyl radicals.
Cycloalkyl radical is understood to mean a cyclic or polycyclic alkane radical containing from 3 to 10 carbon atoms. Preferably, the cycloalkyl radical is chosen from an adamantyl radical or a 1-methylcyclohexyl radical.
Halogen atom is understood to mean preferably a fluorine, chlorine and bromine atom.
Polyether radical is understood to mean a radical having from 2 to 5 carbon atoms which is interrupted by at least two oxygen atoms such as the methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
Among the compounds of formula (I) which fall within the scope of the present invention, the following may be mentioned in particular:
3-Hydroxymethyl-5-{2-[3-(5-hydroxy-5-methylhexyl)phenyl]vinyl}phenol,
3-Hydroxymethyl-5-{2-[3-(6-hydroxy-6-methylheptyl)phenyl]vinyl}phenol,
3-[3-(5-Hydroxy-1,5-dimethylhexyl)phenoxymethyl]-5-hydroxymethylphenol,
6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylhepta-3,5-dien-2-ol,
6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylhexan-2-ol,
6-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-2-methylheptan-2-ol,
7-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-3-ethyloctan-3-ol,
5-{2-[4-(5-Hydroxy-5-methylhexyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[4-(5-Hydroxy-5-methylhexyl)phenyl]ethyl}benzene-1,3-diol,
5-{2-[4-(6-Hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[4-(6-Hydroxy-6-methylheptyl)phenyl]ethyl}benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-6-methylheptyl)phenyl]ethyl}benzene-1,3-diol,
2-Hydroxymethyl-4-{2-[3-(5-hydroxy-5-methylhexyl)phenyl]vinyl}phenol,
2-Hydroxymethyl-4-{2-[4-(5-hydroxy-5-methylhexyl)phenyl]vinyl}phenol,
2-Hydroxymethyl-4-{2-[3-(6-hydroxy-6-methylheptyl)phenyl]vinyl}phenol,
2-Hydroxymethyl-4-{2-[4-(6-hydroxy-6-methylheptyl)phenyl]vinyl}phenol,
2-Hydroxymethyl-4-{2-[3-(5-hydroxy-5-methylheptyl)phenyl]ethyl}phenol,
2-Hydroxymethyl-4-{2-[4-(5-hydroxy-5-methylhexyl)phenyl]ethyl}phenol,
2-Hydroxymethyl-4-{2-[3-(6-hydroxy-6-methylheptyl)phenyl]ethyl}phenol,
2-Hydroxymethyl-4-{2-[4-(6-hydroxy-6-methylheptyl)phenyl]ethyl}phenol,
2-Hydroxymethyl-5-{2-[4-(5-hydroxy-5-methylhexyl)phenyl]vinyl}phenol,
6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylheptan-2-ol,
4-[3-(5-Hydroxy-1,5-dimethylhexyl)phenoxymethyl]-2-hydroxymethylphenol,
6-{3-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylhexan-2-ol,
7-{4-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylheptan-2-ol,
6-{4-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylhexan-2-ol,
5-{2-[3-(6-Hydroxy-6-methylheptyl)phenyl]-1-methylvinyl}benzene-1,3-diol,
5-{2-[3-(5-Hydroxy-5-methylhexyl)phenyl]vinyl}benzene-1,3-diol,
5-[3-(6-Hydroxy-6-methylheptyl)phenoxymethyl]benzene-1,3-diol,
5-{2-[3-(7-Hydroxy-7-methyloct-1-enyl)phenyl]vinyl}-benzene-1,3-diol,
5-{2-[3-(7-Hydroxy-7-methyloctyl)phenyl]vinyl}benzene-1,3-diol,
4-{2-[3-(6-Hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,2-diol,
3-{2-[3-(6-Hydroxy-6-methylheptyl)phenyl]vinyl}phenol,
6-{3-[2-(3,5-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylhexan-2-ol,
3-{2-[3-(7-Hydroxy-7-methyloctyl)phenyl]vinyl}phenol,
7-{3-[2-(3,5-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylheptan-2-ol,
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylheptan-2-ol, 7-{3-[2-(4-Hydroxymethylphenyl)vinyl]phenyl}-2-methylheptan-2-ol,
4-{2-[3-(7-Hydroxy-7-methyloct-1-enyl)phenyl]vinyl}benzene-1,2-diol,
7-[3-(3,4-Bis-hydroxymethylphenylethynyl)phenyl]-2-methylheptan-2-ol,
5-{2-[3-(6-Hydroxy-6-methylhept-1-enyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(7-Ethyl-7-hydroxynon-1-enyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(7-Hydroxy-1-methoxy-1,7-dimethyloctyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-1-methoxy-1,6-dimethylheptyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(5-Hydroxypentyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(5-Hydroxy-6-methylheptyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-7-methyloctyl)phenyl]vinyl}benzene-1,3-diol,
5-{2-[3-(5-Hydroxy-6-methylhept-1-enyl)phenyl]vinyl}-benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-7-methyloct-1-enyl)phenyl]vinyl}-benzene-1,3-diol,
5-{2-[3-(1,6-Dihydroxy-1,6-dimethylheptyl)phenyl]-vinyl}benzene-1,3-diol,
5-{2-[3-(6-Hydroxy-1,6-dimethylhept-1-enyl)phenyl]-vinyl}benzene-1,3-diol,
6-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-methylamino}-2-methylhexan-2-ol,
5-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-methylamino}-2-methylpentan-2-ol,
6-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-methylamino}-3-ethylhexan-3-ol,
7-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-methylamino}-3-ethylheptan-3-ol,
5-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-ethylamino}-2-methylpentan-2-ol,
6-{[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-benzylamino}-3-ethylhexan-3-ol,
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3-ethylocta-4,6-dien-3-ol,
6-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-2-methylhepta-3,5-dien-2-ol,
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-3-ethylocta-4,6-dien-3-ol,
6-{3-[2-(3,4-Bis-hydroxymethylphenyl)vinyl]phenyl}-2-methylhepta-3,5-dien-2-ol,
7-[3-(3,4-Bis-hydroxymethylphenylethynyl)phenyl]-3-ethylocta-4,6-dien-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-3-octanol,
(4E,6E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylocta-4,6-dien-3-ol,
(4E,6Z)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)pheny]-3-ethylocta-4,6-dien-3-ol,
7-[4-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-3-octanol,
(4E,6E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylnona-4,6-dien-3-ol,
(4E,6Z)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylnona-4,6-dien-3-ol,
(E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylhept-3-en-2-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyloct-4-en-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyloct-6-en-3-ol,
(Z)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyloct-6-en-3-ol,
(E)-8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylnon-7-en-2-ol,
(Z)-8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylnon-7-en-2-ol,
(E)-9-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyldec-8-en-3-ol,
(Z)-9-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyldec-8-en-3-ol,
8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methyl-2-nonanol,
9-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyldecan-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyloct-6-en-4-yn-3-ol,
(3E,5E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2,7-dimethylocta-3,5-dien-2-ol,
(4E,6E)-7-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-3-ethyl-octa-4,6-dien-3-ol,
(3E,5E)-6-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-2-methyl-hepta-3,5-dien-2-ol,
(Z)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylnon-6-en-3-ol,
(Z)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methyloct-5-en-2-ol,
(Z)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyldec-6-en-3-ol,
(Z)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methylnon-5-en-2-ol,
(Z)-8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylnon-7-en-3-ol,
(E)-8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-non-7-en-3-ol,
8-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethylnonan-3-ol,
7-[5-(3,4-Bis-hydroxymethylbenzyloxy)-2-methoxyphenyl]-3-ethylnona-4,6-dien-3-ol,
7-[5-(3,4-Bis-hydroxymethylbenzyloxy)-2-methylphenyl]-3-ethylnona-4,6-dien-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)-5-methoxyphenyl]-3-ethylnona-4,6-dien-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)-2-methoxyphenyl]-3-ethylnona-4,6-dien-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)-4-methylphenyl]-3-ethylnona-4,6-dien-3-ol,
1-[3-(3,4)-Bis-hydroxymethylbenzyloxy)phenyl]ethanone O-(2-hydroxy-2-methylpropyl)oxime,
1-{1-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-propoxy}-3-ethylpentan-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-3-ethylnon-6-en-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzylsulfanyl)phenyl]-3-ethyloct-6-en-3-ol,
(E)-7-{3-[(3,4-Bis-hydroxymethylbenzyl)methylamino]-phenyl}-3-ethyloct-6-en-3-ol,
(E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-6-methylhept-4-en-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-7-methyloctan-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3,7-diethylnonan-3-ol,
(E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethyl-oct-5-en-2-ol,
2-{4-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]hexyl}-1,1,1,3,3,3-hexafluoropropan-2-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4,4-difluoronon-6-en-3-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4,4-difluoro-7-methyloctan-3-ol,
(E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-2-methyloct-5-en-3-ol,
(E)-4-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-1-cyclopropylhex-3-en-1-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4-methylnon-6-en-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4-methyldec-6-en-3-ol,
(4E,6E)-7-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-3-ethylnona-4,6-dien-3-ol,
(4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl}-3-ethylnona-4,6-dien-3-ol,
(E)-7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3-ethylnon-6-en-3-ol,
(E)-3-Ethyl-7-[3-(3-hydroxymethylphenoxymethyl)phenyl]non-6-en-3-ol,
(E)-3-Ethyl-7-[3-(4-hydroxymethylphenoxymethyl)phenyl]-non-6-en-3-ol,
(E)-3-Ethyl-7-[(E)-3-(3-hydroxymethyl-4-methylphenoxymethyl)phenyl]non-6-en-3-ol,
(E)-3-Ethyl-7-[(E)-3-(4-hydroxymethyl-3-methyl-phenoxymethyl)phenyl]non-6-en-3-ol,
2-{4-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-4-methylpentyl}-1,1,1,3,3,3-hexafluoropropan-2-ol,
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4,4-difluoro-7-methyl-octan-3-ol,
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3,7-diethylnonan-3-ol
7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-7-methyloctane-3,4-diol
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3,7-diethylnonane-3,4-diol
7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3-ethyl-7-methyloctane-3,4-diol
(E)-4-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-1-cyclopropylhex-3-en-1-ol
(4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-3-ethyl-4-methylnona-4,6-dien-3-ol
(4E,6E)-7-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-3-ethyl-4-methylnona-4,6-dien-3-ol
(E)-3-Ethyl-7-[3-(4-hydroxymethyl-3-methylphenoxymethyl)phenyl]non-6-en-3-ol,
(E)-3-Ethyl-7-[3-(3-hydroxymethyl-4-methylphenoxymethyl)phenyl]non-6-en-3-ol,
(E)-7-[3-(3,4-Bis-hydroxymethylphenoxymethyl)phenyl]-3-ethyloct-6-en-3-ol,
(E)-3-Ethyl-7-[3-(3-hydroxymethylphenoxymethyl)phenyl]-non-6-en-3-ol,
(E)-3-Ethyl-7-[3-(4-hydroxymethylphenoxymethyl)phenyl]-non-6-en-3-ol.
According to the present invention, the compounds of formula (I) which are more particularly preferred are those for which at least one, and preferably all the conditions below are observed:
R1 represents the radical xe2x80x94(CH2)nOH,
R2 represents the radical xe2x80x94(CH2)nOH,
Xxe2x80x94Y represents a bond of formula (a) or (c),
R3 represents a chain of 4 to 8 carbon atoms which is substituted with at least one hydroxyl radical and/or one lower alkyl radical.
The subject of the present invention is also the processes for the preparation of the compounds of formula (I).